Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 628

10.6.2.5 Nuclear Factor- κ B

Nuclear factor- B in endothelial cells has both positive and negative effects on an-

giogenesis [ 1224 ]. According to the context, NF

κ

κ B impedes or promotes apoptosis.

Interactions of α V β 3 -integrin with matrix components that occur during migration

of endothelial cells activate NF κ B factor.

B upregulates VEGF expression as well as vascular endothelial
growth inhibitor. Moreover, NF

Nuclear factor- κ

κ B can bind to angiostatic thrombospondin-1 and -2.

In addition, NF B participates in activation of E-selectin in endothelial cells by

CXCL4 chemokine.
Once NF

κ

κ B is activated by reactive oxygen species and tumor-necrosis factor-

α , it induces expression of plasminogen activator inhibitor PAI1 and can hinder

tissue-type plasminogen activator. 35 On the other hand, NF B promotes expression

of several matrix metallopeptidases (MMP2, MMP3, and MMP9). Consequently,
NF

κ

B can either favor or impede the degradation phase of angiogenesis. Last but
not least, the activity of many angiostatic compounds depends on NF

κ

κ B activation.

10.6.2.6 PPAR γ and PGC1 α Coactivator

Vascular endothelial growth factor operates via both PKC to activate

cAMP-responsive element-binding protein and subsequently produce the pro-
angiogenic enzyme cyclooxygenase-2 in endothelial cells. On the other hand,
nuclear receptor NR1c3, or peroxisome proliferator-activated receptor PPAR

α and PKC β

γ ,

precludes angiogenesis. Factor PPAR γ suppresses membrane translocation of

PKC [ 1225 ].

Regular exercise improves blood circulation in the limbs, as it promotes the
generation of new blood vessels in muscle. Numerous signaling pathways are
activated during exercise that involve PP3 phosphatase, calmodulin-dependent
kinases, AMP-activated protein kinase, stress-responsive P38MAPK, and reactive
oxygen species. All of these pathways impinge on PGC1

α

α [ 1226 ].

Transcriptional PPAR γ coactivator PGC1 α elicits angiogenesis in mus-

cles [ 1226 ]. gene and

promote expression of vascular endothelial growth factor, thereby triggering
angiogenesis. Factor PGC1

β -Adrenergic receptors increase expression of the Pgc1 α

α cooperates with the nuclear receptor estrogen-related

receptor ERR to regulate expression of the VEGF gene [ 1226 ].

In myocytes and adipocytes, the Pgc1

α

gene has an alternative promoter
upstream from the proximal promoter that generates a PGC1

α

isoform with a
few extra N-terminal amino acids. Changes in N-terminus of these proteins may
confer specificity on the angiogenic program [ 1226 ]. Expression of mRNA from

α

35 Plasmin hydrolyzes many extracellular proteins. Urokinase and tissue-type plasminogen acti-
vators have high affinity for inactive plasminogen to produce plasmin. Conversely, plasminogen
activator inhibitors PAI1 and PAI2 prevent the activation of plasminogen into plasmin.